Loss of an ER component, membralin, in astrocytes triggers neuroinflammation.

Abstract

During the progression of Alzheimer's disease (AD), and other neurodegenerative disorders, glial cells including astrocytes and microglia undergo morphological and physiological changes indicative of reactivity. However, whether glial activation is a non-consequential event from pathological stress or alternatively, whether glial activation can contribute to disease pathogenesis is unclear. Endoplasmic reticulum (ER) is the primary cellular organelle for the synthesis of transmembrane and secreted proteins. Previously, we identified an ER protein, membralin, as a novel component of the ER-associated degradation (ERAD) complex. Loss of membralin impaired homeostatic turnover of a key g-secretase complex subunit, nicastrin, resulting in increased g-secretase complex formation and activity, and aggravated AD pathology in TgCRND8 mice. Further, conditional deletion of membralin in astrocytes decreased expression of the excitatory amino acid transporter 2 (EAAT2) and induced excitotoxicity. Using adeno-associated viral (AAV) vectors to elevate membralin levels in the SOD1G93A ALS mouse model can significantly extend the lifespan of these animals. We use RNAseq, electron microscope, primary astrocyte culture, animal models in the study. Analysis of astroglial ER morphology using electron microscope shows that lose of membralin leads to dilated ER, which indicated elevation of ER stress. Transcriptomic analysis of motor cortex from astrocyte-specific membralin knockout animals reveals induction of reactive astrocyte profiles and disease-associated microglia (DAM) signatures. Further, membralin upregulation in astrocytes can alleviate neurotoxic (A1) astrocyte induction. Together, these results indicate that membralin is a critical neuroinflammation regulator. Modulation of astrocyte membralin levels may be promising as a neuroinflammatory suppressor in AD.